The present invention relates to an improved process for the preparation of (4R,6S)-4-hydroxy-6-hydroxymethyl tetrahydro-pyran-2-one of formula (1). 
More particularly the present invention relates to the said process using (S)xe2x88x92(xe2x88x92)xe2x88x92Malic acid.
xcex2-Hydroxy-xcex4-lactones are very important intermediates for the synthesis of a variety of hypocholesterolemic agents (cholesterol lowering drugs). Cholesterol biosynthesis inhibition has become a powerful tool to lower plasma cholesterol high levels. 3-Hydroxy-3-methyl-glutaryl Co-enzyme A (HMGCoA) reductase is a target of choice, because it is the early rate limiting step of the biosynthesis of cholesterol. Mevinolin [2] and Compactin [3] is a specific inhibitor of HMGCoA reductase and is effective in lowering blood plasma cholesterol levels (Endo, A. J. Med. Chem. 1985, 28, 401) 
The important implications for treatment of coronary artery diseases have made these compounds the subject of intense research aimed at biological evaluation and chemical synthesis [Grieco, P. A.; Zelle, R. E.; Lis, R.; Finn, J. J. Am. Chem. Soc. 1983, 105, 1403). The key structural features in HMGCoA reductase inhibitors is the xcex2-hydroxy-xcex4-lactone moiety that is the characteristic of this class of compounds known as mevinic acids which also contains a functionalised decalin unit connected to the lactone via an ethylene bridge. The biological activity is mainly due to the xcex2-hydroxy-xcex4-lactone moiety and the role of decalin units is that of purely hydrophobic in nature.
In the prior-art, the synthesis of key pharmacophore xcex2-hydroxy-xcex4-lactone segment of mevinic acid has been accomplished employing various synthetic strategies. A commonly used strategy for the incorporation of the lactone portion in the synthesis of both the natural materials and synthetic analogs is to employ the masked lactol which can be obtained from carbohydrate degradation (Prugh, J. D. et al Tet Lett 1982, 23, 281; Falck, J. R. Tet Lett 1982, 23, 4305; France, C. J. Tet Lett 1993, 34, 1635) as well as from L-malic acid (Clive D. L. J. Tet Lett 1984, 25, 2101; Guindon, Y. Tet Lett 1985, 26, 1185).
In another prior-art method, the lactone portion is obtained from tri-O-acetyl glucal, which can be derived from carbohydrates [Wareing, James R. (Sandoz, Inc., USA). U.S. Pat. No. 4,474,971, (1984)].
In another prior-art method, the derivatives of title compounds were prepared in 11 steps starting from 3xcex2, 4xcex1-dihydroxy 2xcex1-(hydroxymethyl)-2,3-dihydro-2H-pyranyl triacetate [Jewell, C. F. et al. U.S. Pat. No. 4,625,039 (1986)].
In yet another prior-art method, the synthesis of mevinic acids as well as the synthetic analogs involves the coupling of aryl cuprates with chiral epoxy esters, which can be obtained from a variety of precursors.
In still another prior-art method, the epoxidation of xcex1, xcex2-unsaturated lactones followed by regioselective rupture of the oxirane rings is known to give the xcex2-hydroxy adorned lactone fragment (Ogasawara, K. J. Chem. Soc. Chem. Commun 1989, 539; Ogasawara, K. et al. JP 11240877 (1999); Yadav V. K. I. J. Chem. 34 B, 1995, 1026) In yet another prior-art method, the kinetically controlled iodolactonisation and selenolactonisation strategies are known to give mevinic acid analogues (Bennett, F. et al. J C S Perkin Trans-I 1991, 133, 519 and 1543. Bennett, F. Tet Lett. 1988, 29, 4865).
In another prior-art method, the open chain precursors of the lactone moiety have been generated in optically active forms using chiral starting materials (Repic O, Tet. Lett 1984, 25, 2435), chiral auxiliaries (Lynch J. E. Tet. Lett. 1987, 28, 1385; Dittmer, D. C. J. Org. Chem 1994, 59, 4760) and also enzymatic biocatalyses (Torssell, K. Acta. Chem. Scand, 1977, B 31, 297; Bonini, C. J. Org. Chem. 1991, 4050).
In yet another prior-art method chiral as well as racemic analogs have been prepared using a hetero Diels-Alder reaction (Danishefsky et al al J. Am. Chem. Soc. 1982, 358, 104; Danishefsky, S. et al. J. Org. Chem. 1982, 47, 1981; Bauer, T. J. Chem. Soc. Chem. Comm. 1990, 1178).
Although, the lactone segment has been the target of an increasing number of synthetic efforts, their synthesis remains a challenge. Introduction of the required stereocentres at position C-4 and C-6 of the lactone is vital for the biological activity and has proved to be an important synthetic feature.
Some of the major drawbacks of the methods known in the prior-art are such as
i) multi-step synthesis
ii) high cost of materials involved
iii) complicated reagents, longer reaction time and higher reaction temperature
iv) difficulties involved in the work-up procedures
v) difficulties involved in handling sophisticated reagents
vi) overall low yield of the desired lactone
vii) poor enantio- and diastereoselectivity
viii) lack of reusability of expensive reagents.
In view of the abovementioned drawbacks and disadvantages of the prior art processes, it is desirable to develop an improved, efficient and enantioselective process for the synthesis of (4R,6S)-4-hydroxy-6-hydroxymethyl tetrahydro-pyran-2-one.
The object of the present invention is to provide an improved, efficient and enantio-selective process for the synthesis of (4R,6S)4-hydroxy-6-hydroxymethyl tetrahydro-pyran-2-one, which overcomes the drawbacks of the prior-art processes employing the Sharpless asymmetric dihydroxylation and regiospecific nucleophilic hydride opening of the cyclic sulfite/sulfate as the key steps.
The significant feature of the present invention is:
i) The process relatively involves less number of steps.
ii) The reactions involved in each step, according to the present invention, could be carried out relatively at lower temperature or room temperature.
iii) The process leads to high yields of the desired products.
iv) All possible stereoisomers of the desired lactone could be prepared using this process.
v) The process gives high enantio-and diastereoselectivity of the products.
vi) The chiral ligands used to induce chirality could be recovered.
The process of the present invention is described in details in the schematic diagram herein below 
Accordingly, the present invention provides an improved, efficient and enantioselective process for the synthesis of (4R,6S)-4-hydroxy-6-hydroxymethyl tetrahydro-pyran-2-one which comprises
i) reacting the (S)-(xe2x88x92)-Malic acid with a mixture of mineral acid and alcohol at room temperature for a period of 18 to 30 hrs to obtain the diester of (S)-(xe2x88x92)-Malic acid of formula (4)
ii) reducing the compound (4) with a hydride reducing reagent at room temperature to reflux temperature for a period of 8 to 12 hrs to obtain (S)-1,2,4-butanetriol of formula (5)
iii) treating the compound (5) with protecting reagent at room temperature for a period of 36 to 48 hrs to obtain (S)-1,2,4-butanetriol 1,2-acetonide of formula (6)
iv) oxidizing compound (6) using oxidizing reagents at xe2x88x9278xc2x0 C. for a period of 1 to 2 hrs to obtain the aldehyde in situ, treating the aldehyde with a phosphorus ylide at room temperature for a period of 18 to 24 hrs to obtain (5S)-trans-5,6-dihydroxy-2-hexenoate 5,6-acetonide of formula (7)
v) treating compound (7) with osmium tetraoxide and a chiral ligand at 0xc2x0 C. for a period of 12 to 24 hrs to obtain (2S,3R,5S)-ethyl-trans-2,3,5,6-tetrahydroxy-hexenoate 5,6-acetonide of formula (8)
vi) treating compound (8) with a halide of sulphuryl or thionyl reagent at 0xc2x0 C. for a period of 30 to 40 mins to obtain (4R)-carbethoxy-(5S)-di-O-isopropylidine propyl-1,3,2-oxathiolane-2-oxide of formula (9)
vii) reacting the compound (9) with a hydride based reagent at room temperature in inert atmosphere for a period of 8 to 12 hrs, hydrolyzing the reaction mixture with a mineral acid to obtain the product of formula (1)
In one of the embodiments of the present invention the mineral acid used in (i) and (vii) may be sulphuric, hydrochloric, toluene sulphonic or trifluoroacetic acid, preferably hydrochloric acid.
In another embodiment the alcohol used in (i) may be alkyl alcohols exemplified by methanol, ethanol, iso-propanol, butanol preferably methanol.
In still another embodiment the reducing agent used in (ii) and (vii) may be hydrides of alkali metals exemplified by sodium borohydride, lithium borohydride, sodium cyanoborohydride and lithium aluminum hydride preferably lithium aluminum hydride/sodium borohydride.
In yet another embodiment the protecting reagent in (iii) may be acetone, 3-pentanone, 2,2-dimethoxy propane and cyclohexanone preferably 2,2-dimethoxy propane.
In another embodiment the oxidizing agent used in (iv) may be an oxidizing agent conventionally used for oxidizing an alcohol to aldehyde such as mixture of oxalyl chloride and dimethyl sulphoxide (DMSO), phosphorus pentoxide and DMSO, pyridinium chlorochromate, pyridinium dichromate and manganese dioxide, preferably mixture of oxalyl chloride and DMSO.
In still another embodiment the phosphorus ylide used in (iv) may be (ethoxycarbonylmethylene)triphenylphosphorane, trimethyl phosphonoacetate, triethyl phosphonoacetate, ethyl-dimethyl phosphonoacetate, preferably (ethoxycarbonylmethylene)triphenylphosphorane.
In yet another embodiment the chiral ligands may be one of the 1st or 2nd generation mono- or bidentate ligands such as phthalazine, pyrimidine, phenanthryl, quinoxaline, p-chlorobenzoate, preferably phthalazine.
The invention also resides in the novel intermediates used in the process.
One of the novel intermediate is (2S,3R,5S)-ethyl-trans-2,3,5,6-tetrahydroxy-hexanoate 5,6-acetonide having of formula (8) 
the other novel intermediate is (4R)-carbethoxy-(5S)-di-O-isopropylidine propyl-1,3,2-oxathiolane-2-oxide having of formula 
In a feature of the present invention, in order to make all possible stereoisomers of 6-hydroxymethyl-4-hydroxy-o-lactone, a variety of ligands used in the Sharpless asymmetric dihydroxylation procedure were procured from Aldrich Co.